Great question — and very relevant to modern drug delivery systems like oral thin films!

When a hydrophilic drug (that is not lipid-soluble) is used in oral film formulations, it faces the lipophilic barrier of the oral mucosa, which naturally resists water-soluble compounds. However, several mechanisms and formulation strategies can help it cross the mucosal barrier and reach systemic circulation.

🔍 What Happens in the Case of Oral Film with a Hydrophilic API? 1. Primary Absorption Route: Paracellular Pathway

Hydrophilic drugs typically move between mucosal cells, through tight junctions.

This is a slow and limited process.

Works better for small, uncharged molecules.

🔹 Example: Nicotine and some small peptides have shown paracellular absorption via oral mucosa.

⚙️ How Formulations Help Hydrophilic Drugs in Oral Films 2. Use of Permeation Enhancers

Oral films often contain permeation enhancers to:

Temporarily loosen tight junctions

Increase fluidity of the membrane

Examples:

Chitosan

Surfactants (e.g., Polysorbate 80)

Fatty acids, bile salts

These enhancers improve drug diffusion even if the drug is hydrophilic and not lipid-soluble.

3. Mucoadhesive Polymers

Polymers like HPMC, carbopol, or pectin in the film help it stick longer to mucosal tissue.

Longer contact time = greater absorption window for the drug.

4. pH Modifiers in the Film

Local pH can be adjusted to favor the non-ionized form of the drug, improving its ability to pass the mucosal barrier.

5. Encapsulation or Nanotechnology

Drug can be loaded into nanoparticles, liposomes, or micelles:

These systems shield the hydrophilic nature.

Allow better penetration across mucosa.

Once past the barrier, the carrier releases the drug into the bloodstream.

🔄 Alternate Fate: Swallowing

If the drug doesn’t absorb through mucosa, it may be:

Swallowed with saliva, then absorbed via GI tract.

But this leads to first-pass metabolism in the liver, reducing bioavailability.

Hi !

In oral films, a hydrophilic and non-lipid-soluble drug crosses the oral mucosa mainly via the paracellular route, which is inherently limited due to tight junctions. To enhance permeation, permeation enhancers, mucoadhesive polymers, and nanoformulations (e.g., nanoparticles, cyclodextrin complexes) are incorporated to transiently loosen tight junctions and increase residence time.

References in support:

🔗 PubMed - Oral Mucosal Drug Delivery, Article The Science and Economics of Improving Clinical Communication

Article Orotransmucosal drug delivery systems: A review

A hydrophilic (water-soluble) drug has difficulty crossing the oral mucosa because it does not dissolve in lipids and cannot easily pass through the lipid-rich cell membranes. However, it can cross the mucosal barrier via two main pathways:

Paracellular route:

The drug passes between cells through tiny gaps called tight junctions. However, these junctions are very narrow in the oral mucosa, so only a small amount of drug can pass, resulting in low absorption.

Transporters or permeation enhancers:

Formulation can include substances that open tight junctions or increase membrane fluidity, allowing the drug to pass more easily through or between cells. Sometimes, specific transport proteins help carry the drug into the cell.